Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains

Definitions

• the esterification of the acids (a) to (e) can also be carried out under acidic catalysis without removing the water of reaction at medium temperatures and short reaction times, if 8 to 15 mol of diethylene glycol, preferably 10.5 to 12, per mole of acid Mol can be used.
• Suitable acidic catalysts are Lewis acids, zinc chloride, sulfuric acid, phosphoric acid, polyphosphoric acid, benzenesulfonic acid, p-toluenesulfonic acid or mixtures of phosphoric acid and p-toluenesulfonic acid, in molar ratios of 0.1 to 1.0 mol of catalyst per mol of acid.
• the reaction temperature is 60 * to 120 °, preferably 80 to 100 'with reaction times of 1 to 5 hours.
• reaction water remaining in the batch allows such a high ester yield, since, according to the current teaching, on which DE-PS 28 34 167 is based, the reaction equilibrium is shifted in favor of the ester, and the water of reaction is removed. azeotropic orbiting is required.
• the excess of diethylene glycol after neutralization with alkali or alkaline earth metal hydroxides or carbonates optionally added in solid form is removed by distillation or advantageously by adding water, the crude ester separating out or being obtained by extraction with suitable solvents.
• the crude ester obtained is either distilled in a two-stage vacuum short-path distillation system or purified by means of preparative medium-pressure liquid chromatography over conventional sorbents, preferably silica gel. Pressures of 10-20 bar are suitable.
• the diethylene glycol monoesters according to the invention have anti-inflammatory properties. They can be used in medicinal products, whereby the concentration and dosage correspond to those of the known basic acid bodies.
• the anti-inflammatory properties of the new esters were measured in comparison to the respective standard in the rat's paw edema test.
• the inhibitory effect relates to the respective value of the untreated control group to which the vehicle was administered. The results are summarized in Table 1.
• the new esters are effectively superior to the respective acid as a standard.
• the same inhibitory effect is achieved after oral administration with a significantly reduced dose of the esters or is more pronounced (Lonazolac).
• the esters with equimolar dosing are clearly superior within the measurement period.
• esters according to the invention are used in pharmaceuticals for dermal use in concentrations of 1 to 20% by weight, preferably 5 to 10% by weight.
• Suitable dermal formulations are ointments and creams of the oil-in-water (O / W) or water-in-oil (W / O) type using conventional salve bases and auxiliaries, such as fat components, emulsifiers and stabilizers, and also gels using Tylose, Carboxymethyl cellulose, salts of acrylic acid polymers or acrylic acid-acrylamide copolymers as structuring agents in aqueous or alcoholic aqueous preparation forms, and solutions in dermally compatible solvents, such as alcohol, alcohol-water mix. or fatty alcohols and esters.
• dermal formulations which additionally contain penetration mediators, such as dimethyl sulfoxide in concentrations of 10 to 40% by weight or urea with 5 to 10% by weight.
• penetration mediators such as dimethyl sulfoxide in concentrations of 10 to 40% by weight or urea with 5 to 10% by weight.
• the pharmaceuticals thus produced are used to combat diseases of the rheumatic type.
• the diethylene glycol monoesters from Lonazolac and Diciofenac are particularly preferred.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Rheumatology (AREA)
• Pain & Pain Management (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)

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• 1988
  • 1988-03-31 DE DE3811118A patent/DE3811118C1/de not_active Expired
• 1989
  • 1989-03-14 EP EP19890104496 patent/EP0336147A3/fr not_active Withdrawn
  • 1989-03-23 FI FI891409A patent/FI891409A/fi not_active IP Right Cessation
  • 1989-03-27 KR KR1019890003842A patent/KR890014105A/ko not_active Application Discontinuation
  • 1989-03-30 JP JP1076844A patent/JPH026432A/ja active Pending
  • 1989-03-31 US US07/331,124 patent/US4960793A/en not_active Expired - Fee Related

Patent Citations (2)

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